The Role of Leukocytes

The role of leukocytes in CVI was demonstrated by the increased number of cells in the dermis of patients with lipodermatosclerosis and healed ulceration.18 Further work in this area aimed to define cell type and function responsible for the formation of the dermal skin fibrosis and ulceration. In a study evaluating the number of white blood cells in tissue biopsies of patients with CVI, it was determined that the number of leukocytes was highest in the dermis of patients with a history of ulceration followed by tissue with lipodermatosclerosis, and lowest in patients with uncomplicated skin and CVI.21 A careful histological study using immunohistochemistry in patients with severe lipodermato-sclerotic skin changes determined that the predominant cell types were T lymphocytes and macrophages, and expression of intercellular adhesion molecule-1 was elevated but not endothelial leukocyte adhesion molecule-1 or vascular cell adhesion molecule and rarely were neutrophils observed, concluding that the accumulation of macrophages and T lymphocytes are associated with CVI skin changes and ulceration.22 To further evaluate the activity of circulating markers on leukocytes in patients with CVI and confirm prior findings of dermal tissue histological findings, a study determined that compared to normal control patients, patients with CVI had decreased CD3+/CD38+ markers on T-lymphocytes and increased expression of CD14+/CD38+ markers on monocytes, and no neutrophil activation was present.23 Function of mononuclear cells was evaluated by proliferation response in the presence to staphylococcal enterotoxins antigen challenge. The study concluded that mononuclear cell function deteriorated with CVI, and that diminished proliferative response was observed with greater severity of CVI disease (venous ulcers and lipodermato-sclerosis), indicating that decrease mononuclear cell proliferation may be involved in poor wound healing.24 In a quantitative study utilizing electron microscopy evaluating differences in endothelial cell structure, leukocyte cell type and their relationship to the microcirculation in dermal biopsies of patients with advanced CVI was investigated. The authors determined that patients with severe lipoderma-tosclerosis and healed ulcers contained a significant number of mast cells around arterioles and postcapillary venules, and in active ulcers macrophages were predominant in the postcapillary venule. Fibroblasts were the most abundant cell type in all biopsies evaluated without any differences of severity of disease, and no differences in interendothelial junctions widths were observed.25

The involvement of leukocytes in CVI pathology requires leukocyte/endothelial signaling for the cells to extravasate and enter the dermal tissue. A study evaluating changes in adhesion molecules in patients with severe lipodermatoscle-rosis and active ulceration by immunohistochemistry of biopsies adjacent to ulcerated skin demonstrated that increased expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 was present. In addition, the expression of leukocyte function-associated antigen-1 and very late activated antigen-4 was increased dramatically on perivascular leukocytes compared to healthy skin indicating that the upregulation of adhesion molecules in CVI patients are important mediators toward facilitating leukocyte endothelial adhesion, activation, and transendothelial migration.26

Although the evidence suggests that neutrophils rarely are found in the dermis of patients with severe CVI and that activation has not been detected, several studies have identified a role for neutrophils in CVI. Investigators evaluating patients with varicose veins with and without skin changes took blood samples from dependent legs in the foot in the supine position. Leukocyte surface marker CD11b and L-selectin expression were analyzed by flow cytometry, and plasma soluble L-selectin was measured by ELISA. In dependent legs with skin changes, both the median neutro-phil and monocyte CD11b and L-selectin levels decreased and remained low after venous hypertension was reversed

Advanced CVI: Lipodermatosclerosis and Venous Ulcers

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